Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation

Abstract

Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169 macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169 macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2-related factor 2-dominant, cytoprotective/antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation.

Functional Urate-Associated Genetic Variants Influence Expression of lincRNAs LINC01229 and MAFTRR

“…MAF function is important for the development and differentiation of the proximal tubule cells (Imaki et al, 2004). Additionally MAF has been shown to regulate antioxidant (Dhakshinamoorthy and Jaiswal, 2002; Kikuchi et al, 2018) and apoptotic pathways (Peng et al, 2007) that are required for NLRP3 inflammasome activation implicated in chronic kidney disease and gout (Jhang and Yen, 2017; So and Martinon, 2017). Although there are multiple genetically independent signals associated with serum urate levels in a ∼500 kb region upstream of the MAF gene (Figure 1), it is not known if these influence the expression of MAF .…”

The BACH1–HMOX1 Regulatory Axis Is Indispensable for Proper Macrophage Subtype Specification and Skeletal Muscle Regeneration

“…To our knowledge, only three other experimental systems (DUSP1, AMPKa1, or IGF1 deficiency in muscleinfiltrative MFs) were reported to lead to altered MF phenotype switch (18)(19)(20). Furthermore, it has been recently suggested that one of the MARE family TFs, Maf (also active in our experimental system), upon exposure to pathogens, can promote an acute inflammatory response although suppressing both NFE2L2 activity and conversion to a cytoprotective phenotype in colon CD169 + and BMDMs (69).…”

Single cell RNA sequencing identifies unique inflammatory airspace macrophage subsets

“…In support of this hypothesis, cluster 3 demonstrates increased expression of proapoptotic caspase 8, while cluster 4 is notable for increased expression of antiapoptotic molecules, Bcl2L1, Ier1, mitogen-activated protein kinase 2 (MAPK2), and Mapk14 (p38) (55). Likewise, cluster 4 cells express high levels of Nrf2 and its downstream products, Slc7a11 and Slpi, genes implicated in cytoprotective and antioxidant functions (56).…”